Dr. Joan Mannick - Targeting mTOR to Improve Immune Function and Healthspan (May 2025)

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AI Summary

Longevity Roadmap – Interview with Dr. Joan Manick on Targeting mTOR for Immune‑Boosting and Health‑Span Extension

1. Who is Dr Joan Manick?

  • Physician‑scientist and biotech entrepreneur.
  • Harvard MD; faculty positions at Harvard and UMass.
  • Co‑founder of Restore Bio (led trials of mTOR‑inhibitor RTB‑101 to enhance immunity in older adults).
  • Current CEO of Tornado Therapeutics, developing next‑generation, TORC1‑selective mTOR inhibitors for safe, long‑term use.

2. Why mTOR?

  • mTOR is the central cellular sensor of nutrients; it drives growth when active.
  • Inhibition of mTOR (especially TORC1) triggers protective, “clean‑up” pathways (autophagy, stress resistance).
  • Across species—yeast, worms, flies, mice, and monkeys—genetic or pharmacologic TORC1 inhibition extends lifespan, suggesting relevance to humans.

3. TORC1 vs. TORC2

  • TORC1 mediates the longevity‑beneficial effects (cellular cleaning, autophagy).
  • TORC2 inhibition produces undesirable metabolic side‑effects: hyperlipidemia, hyperglycemia, and even reduced lifespan in animal models.
  • Ideal drugs should selectively inhibit TORC1 while sparing TORC2.

4. Rapamycin and Dosing Strategies

  • Classic rapamycin (rapalog) primarily blocks TORC1; chronic/high doses begin to affect TORC2.
  • Low‑dose or intermittent regimens (e.g., 6‑8 mg once per week) aim to capture TORC1 benefits while minimizing TORC2‑related toxicity.
  • This “pulsatile” approach is widely used in the longevity community.

5. Clinical Proof‑of‑Concept: Immune Enhancement

  • Goal: find a rapid, measurable outcome for an aging‑targeted drug. The immune response to vaccination fit the bill.
  • Study 1 – Flu‑vaccine response: Low‑dose TORC1 inhibition in older adults improved antibody titers and reduced T‑cell exhaustion (lower PD‑1+ CD4/CD8), likely via enhanced autophagy and better antigen presentation.
  • Study 2 – RTB‑101 (TORC1‑selective catalytic inhibitor): Showed similar boost to flu‑vaccine responses; intended as a proof that TORC1 modulation can revitalize immune function.

6. Broader Application: Seasonal Respiratory‑Infection Trial

  • Hypothesis: TORC1 inhibition could lower incidence/severity of all respiratory viral infections in elders (beyond flu).
  • Phase 2 showed a reduction in laboratory‑confirmed infections; Phase 3 changed the primary endpoint to symptom‑based reporting (per FDA guidance), leading to a missed statistical goal.
  • Lessons learned: objective virologic confirmation is essential; the drug appears to dampen severity rather than prevent infection outright.

7. Muscle Considerations

  • mTOR activation is needed for muscle protein synthesis; chronic hyper‑activation with age impairs the normal on/off rhythm.
  • TORC1 inhibition in older animals paradoxically improved some muscle mass and neuromuscular function, suggesting that restoring the proper oscillation of mTOR activity benefits sarcopenia.

8. Current & Future Pipeline

  • Tornado Therapeutics is advancing TORC1‑selective rapalogs (refined chemistry, higher selectivity, better safety) into Phase 1 safety studies.
  • Planned indications include: immune rejuvenation, age‑related metabolic decline, and other geriatric syndromes where mTOR hyper‑activity is implicated.

9. Perspective on Supplements & Other Longevity Targets

  • Dr. Manick stresses the importance of placebo‑controlled data; many over‑the‑counter “longevity” supplements lack rigorous trials.
  • While she acknowledges other promising avenues (e.g., epigenetic reprogramming, NADâș biology), mTOR remains the most experimentally validated target with cross‑species lifespan data.

10. Vision If Funding Were Unlimited

  • Conduct comprehensive human trials to map optimal dose, schedule, and tissue distribution of TORC1‑selective inhibitors across multiple age‑related diseases.
  • Combine deep AI‑driven comparative genomics (long‑lived vs. short‑lived species) with drug development to pinpoint additional longevity genes.

Take‑away:
Dr. Joan Manick’s work positions TORC1‑selective inhibition as a clinically tractable strategy to rejuvenate the aging immune system and potentially improve overall health‑span, while avoiding the metabolic drawbacks of non‑selective mTOR blockade. Ongoing trials and next‑generation molecules aim to translate the robust pre‑clinical lifespan data into safe, effective therapies for older adults.

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